FDA Treads Delicate Line Between Safety and Speed

Friday, January 1, 1999

Volume:

13

Issue:

1

The FDA uses a complex series of procedures to
get needed drugs to patients as quickly as possible while ensuring
safety. Patricia Keegan, md, oncology staff director in the FDAs
Clinical Trial Design and Analysis Division, walked the audience
through several of these procedures at the 89th Annual Meeting of the
American Association for Cancer Research.

The standard study procedure for a possible new drug consists of
three or four phases of clinical trials that the drug must pass
through successfully to win FDA approval. However, special provisions
for drugs meant for serious and life-threatening diseases allow these
agents to get to market faster.

Standard Clinical Trials Process

Dr. Keegan described the standard series of clinical trials. As she
noted, the purpose of the phase I trial is to determine a drugs
dose range and toxicity. Because cancer drugs are generally toxic and
because the correct doses are not yet known, phase I trials are
usually conducted in people with cancer, in whom the possible
benefits help offset the risks.

Once a tolerable dose range has been established, phase II trials
determine the drugs activity. At this stage, researchers may do
further exploration of the dose range in patients with measurable
disease. Because the goal is to test how well the drug works,
researchers need to be able to tell whether the drug is improving or
worsening the disease.

When phase II trials demonstrate some effectiveness, Dr. Keegan said,
the drug may advance to phase III trials. In order to test the new
drugs safety and effectiveness, these clinical trials compare
it with a placebo or standard therapy. Usually, the goal is to show
that the new drug works at least as well as no drug at all and as
well as or better than existing drugs.

After phase III trials, the company may submit an application to the
FDA for approval. In evaluating potential cancer drugs, the FDA
typically looks for evidence that the treatment extends the
patients survival or that it eases symptoms and thereby
improves the patients well-being.

If approval is granted, the company may conduct a series of phase IV
trials after the drug is on the market. These new trials again focus
on safety and efficacy, this time in a broader population. The
manufacturer can also obtain information on delayed or sustained effects.

Faster Approval Possible

When there is an unusually great need for a drugfor example,
when it is meant for a serious or life-threatening disorder for which
there is no good existing therapythe FDA offers three ways to
get drugs to patients faster: expedited review, accelerated approval,
and fast-track approval.

Expedited ReviewIn expedited review, also known as
subpart E status, the company can apply for approval based on
well-executed and well-controlled phase II trials that showed
efficacy. In general, the FDA would require phase IV trials for a
drug approved under expedited review.

Accelerated ApprovalIn accelerated approval, the company
applies for conditional approval based on the demonstration of
meaningful therapeutic benefit over existing therapies, Dr.Keegan
said. The FDA might set certain restrictions on the drug to ensure
safety and could withdraw approval if those conditions are not
followed. As in expedited review, the FDA may require phase IV trials
to continue to study the drug after approval.

Fast-Track ApproachThis process is meant for drugs that
have demonstrated potential to fulfill an unmet medical need.
Companies who have applied for fast-track status for a drug can also
apply for rolling application. This means that the
company can submit its marketing application in pieces as each is
finished, rather than waiting until the application is complete.

Getting Investigational Drugs to Patients

Dr. Keegan briefly listed a few ways that the FDA is helping patients
get expanded access to agents under investigation. One example is the
single-patient investigational new drug (IND) application. A
researcher can apply for permission to give a specific named patient
the investigational drug even though the patient does not meet all of
the requirements for joining a clinical trial.

The FDA may allow the patient to receive the drug if three conditions
are met: The manufacturer is willing to supply the drug, a physician
is willing to administer it, and the patient is willing to take it
(as shown by signing a consent form).

Dr. Keegan stressed that drug manufacturers fare best if they stay in
close contact with the agency from the very beginning of drug
development. The FDA can guide the company with respect to what must
be done to get approval. For example, it is important to have a
meeting with the FDA before the first IND application is even filed.
The agency can advise the company as to what it expects to see in the
IND application, and the FDA and the company can iron out problems
and come to an agreement on the study end points.

Dr. Keegan explained that these meetings can often be conducted by
conference calls or videoconferencing rather than in person. For
companies that would like to take advantage of expedited review,
accelerated approval, or fast-track approval, staying in close touch
with FDA is even more crucial.